Ortho ester

The general formula of orthoesters.

In organic chemistry, an ortho ester is a functional group containing three alkoxy groups attached to one carbon atom, i.e. with the general formula RC(OR′)₃. Orthoesters may be considered as products of exhaustive alkylation of unstable orthocarboxylic acids and it is from these that the name 'ortho ester' is derived. An example is ethyl orthoacetate, CH₃C(OCH₂CH₃)₃, more correctly known as 1,1,1-triethoxyethane.

Synthesis

Ortho esters can be prepared by the Pinner reaction, in which nitriles react with alcohols in the presence of one equivalent of hydrogen chloride. The reaction proceeds by formation of imido ester hydrochloride:

RCN + R′OH + HCl → [RC(OR′)=NH₂]⁺Cl⁻

Acid chlorides can also drive the reaction from the corresponding amide, e.g.:

HCONH₂ + ROH + BzCl → HC(OR)₃ + NH₄Cl BzOH.

Upon standing in the presence of excess alcohol, this intermediate converts to the ortho ester:

[RC(OR′)=NH₂]⁺Cl⁻ + 2 R′OH → RC(OR′)₃ + NH₄Cl

The reaction requires anhydrous conditions, and ideally a nonpolar solvent.

Although a less common method, ortho esters were first produced by reaction of 1,1,1-trichloroalkanes with sodium alkoxide:

RCCl₃ + 3 NaOR′ → RC(OR′)₃ + 3 NaCl

Likewise, traditional esters can be converted to α,α‑dichloro ethers with phosphorus pentachloride. The resulting halogenated compounds undergo ether synthesis as above. Compounds with an adjacent hydrogen atom on R tend to undergo elimination instead.

Carboxylic acids naturally form a trithio ortho ester when heated with a mercaptan of appropriate stoichiometry. The resulting compound undergoes transesterification to a traditional orthoester in the presence of zinc chloride. Traditional transesterification from a cheaper ortho ester is also possible.

Reactions

Hydrolysis

Ortho esters are readily hydrolyzed in mild aqueous acid to form esters:

RC(OR′)₃ + H₂O → RCO₂R′ + 2 R′OH

For example, trimethyl orthoformate CH(OCH₃)₃ may be hydrolyzed (under acidic conditions) to methyl formate and methanol; and may be further hydrolyzed (under alkaline conditions) to salts of formic acid and methanol.

Johnson–Claisen rearrangement

The Johnson–Claisen rearrangement is the reaction of an allylic alcohol with an ortho ester containing a deprotonatable alpha carbon (e.g. triethyl orthoacetate) to give a γ,δ-unsaturated ester.

Bodroux–Chichibabin aldehyde synthesis

In the Bodroux–Chichibabin aldehyde synthesis an ortho ester reacts with a Grignard reagent to form an aldehyde; this is an example of a formylation reaction.

Examples

Hygromycin B, an antibiotic, is one of several naturally occurring ortho esters.

OBO: 4-methyl-2,6,7-trioxa-bicyclo[2.2.2]octan-1-yl

Examples of orthoesters include the reagents trimethyl orthoformate and triethylorthoacetate. Another example is the bicyclic OBO protecting group (4-methyl-2,6,7-trioxa-bicyclo[2.2.2]octan-1-yl) which is formed by the action of (3-methyloxetan-3-yl)methanol on activated carboxylic acids in the presence of Lewis acids. The group is base stable and can be cleaved in two steps under mild conditions, mildly acidic hydrolysis yields the ester of tris(hydroxymethyl)ethane which is then cleaved using e.g. an aqueous carbonate solution.

The threefold symmetry of the cyclohexanehexol isomer scyllo-inositol (scyllitol) yields the triply-bridged orthoformate esters scyllitol orthoformate with an adamantane-like skeleton, and scyllitol bis-orthoformate with two fused adamantane-like skeletons.

See also

• Acetal, C(OR)₂R₂
• Orthocarbonate, C(OR)₄.